Abstract 5030: Treatment of aromatase inhibitor-resistant cells with polyisoprenylated cysteinyl amide inhibitors stimulates the mitogen-activated protein kinase pathway enzymes, impedes cell proliferation and causes cell death

Abstract

Abstract Overexpression and hyperactivity of the estrogen receptor drives 67-80% and 90% of breast cancer in women and men, respectively. Resistance to aromatase inhibitor (AI) therapies necessitates the continuous search for novel therapies. Previous studies demonstrate AI-resistance is associated with hormone-independence, enhanced motility, and increased growth factor signaling. Here, long-term letrozole-treated (LTLT-Ca) breast cancer cells were used to evaluate polyisoprenylated cysteinyl amide inhibitors (PCAIs) as potential alternative therapies for the treatment of aromatase inhibitor-resistant breast cancer. We determined the potency of PCAIs as anticancer agents by evaluating their effects on cell viability, phosphorylation of MAPK pathway enzymes, G-proteins levels, cell migration and apoptosis. Among the PCAIs tested, NSL-YHJ-2-27 showed significant potency against cell viability with an EC50 of 3.6 µM. MEK (p-MEK1/2), ERK (p-ERK1/2), and p90RSK (p-p90RSK) phosphorylation were significantly increased by 178, 119 and 125%, respectively, over controls. In addition, of the seven G-proteins evaluated, only KRAS and NRAS showed significant increases of 49% and 97%, respectively. Cell proliferation and colony formation were impeded by 82% and 74%, respectively, after PCAIs treatment. Migration of the LTLT-Ca cells was inhibited by 80% following treatment with 5 µM of NSL-YHJ-2-27. Lastly, the PCAIs also caused the degeneration of the spheroids after 10 µM PCAIs treatment, dead cells were very apparent after AO/EB staining. Our findings suggest that the PCAIs’ suppression of cell viability and activation of the MAPK pathway causes apoptosis possibly through the activation of the proapoptotic p-p90RSK isoforms. The results reveal the ability of the PCAIs to effectively cause a negative impact on several cancer hallmarks suggesting their potency as anticancer agents. These findings also support a potential role for PCAIs’ use in treating breast cancers that have become resistant to aromatase inhibitor therapies. Citation Format: Jassy Mary S. Lazarte, Syreeta L. Tilghman, Nazarius S. Lamango. Treatment of aromatase inhibitor-resistant cells with polyisoprenylated cysteinyl amide inhibitors stimulates the mitogen-activated protein kinase pathway enzymes, impedes cell proliferation and causes cell death. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5030.